The composite solubility versus pH profile and its role in intestinal absorption prediction

The purpose of this study was to examine absorption of basic drugs as a function of the composite solubility curve and intestinally relevant pH by using a gastrointestinal tract (GIT) absorption simulation based on the advanced compartmental absorption and transit model. Absorption simulations were carried out for virtual monobasic drugs having a range of pKa, log D, and dose values as a function of presumed solubility and permeability. Results were normally expressed as the combination that resulted in 25% absorption. Absorption of basic drugs was found to be a function of the whole solubility/pH relationship rather than a single solubility value at pH 7. In addition, the parameter spaces of greatest sensitivity were identified. We compared 3 theoretical scenarios: the GIT pH range overlapping (1) only the salt solubility curve, (2) the salt and base solubility curves, or (3) only the base curve. Experimental solubilities of 32 compounds were determined at pHs of 2.2 and 7.4, and they nearly all fitted into 2 of the postulated scenarios. Typically, base solubilities can be simulated in silico, but salt solubilities at low pH can only be measured. We concluded that quality absorption simulations of candidate drugs in most cases require experimental solubility determination at 2 pHs, to permit calculation of the whole solubility/pH profile

The brachiopod <i>Eoobolus</i> from the early cambrian mural formation (Canadian Rocky Mountains)

The Early Cambrian brachiopod, Eoobolus, is one of the first representatives of the superfamily, Linguloidea, the defining characteristics of which include the classical morphology of oval shells and a pedicle that emerges from between the two valves. The material described here from the Mural Formation (Jasper National Park, Canadian Rocky Mountains) provides well-preserved muscle scars and larval shells that allow a discussion of the muscle system and the larval morphology of Eoobolus. The dorsal larval shell exhibits a morphology similar to other Cambrian linguloids, but also to paterinids, Mickwitzia muralensis, and some rhynchonelliforms. This suggests that there was a lesser degree of disparity among brachiopod larvae in the Cambrian than there is today. The muscle system of Eoobolus is similar to other linguloids, but differs from that of Recent lingulids and discinids by having one or two more pairs of oblique muscles. New data on the distribution of features characteristic of the family Eoobolidae question the validity of this family